Project 1: Modeling hyper-excitability in neurological disease using patient-derived pluripotent stem cells ABSTRACT Bipolar disorder (BP) is a multigenic neuropsychiatric disorder affecting 1-4% of the adult population in the United States. BP patients suffer from oscillations between episodes of severe mania and depression, and 15% of patients commit suicide without treatment. Although current animal-based research models and post- mortem analysis have provided important information related to genetic alterations and cellular phenotypes of BP, the intrinsic limitations of these tools have challenged pathological research and drug development. For instance, none of the current BP animal models can recapitulate both manic and depressive phenotypes or cycling of BP simultaneously. Therefore, it is an urgent task to develop accurate and efficient biological models for BP. Induced pluripotent stem cell (iPSC) technology has been widely used to model neuronal disorders. For complex neurodevelopmental disorders such as BP, the iPSC model is an ideal tool for pathological study and drug screening because the neurons differentiated from patient-derived iPSCs carry the natural genetic background of multigenic diseases and can be studied under modulated experimental conditions. We have generated iPSCs from BP-affected and unaffected individuals, and differentiated them into dentate gyrus granule cells of the hippocampus. We found phenotypes of increased neuronal activity, which can be reduced to control levels by lithium treatment selectively in the lithium-responsive subset of BP patient-derived neurons. In the current project, we propose to further investigate the hypothesis that neurons from BP patients are hyper-excitable by extending the analysis to include different neuronal subtypes and astrocytes, and increasing our patient cohort size. We will additionally investigate the effects of this hyperactivity on mitochondrial function and neuronal survival, implicated in BP by both clinical observations and our RNA sequencing results. We will integrate our findings with data from the investigation of other BP cohorts at partner sites. We may also identify commonalities underlying distinct psychiatric disease through comparison with schizophrenia-associated iPSC cohorts. Our goal is to validate the iPSC model of BP by verifying the cellular phenotypes of the disease and to apply this model to the development of robust high throughput assays that can be used for discovery purposes.